lessons learned from heart failure trials with respect to renal …€¦ · 04-02-2017 · lessons...

LessonsLearnedfromHeartFailureTrialswithRespecttoRenalOutcomes

JavedButler,MDMPHMBAProfessorofMedicine

ProfessorofPhysiologyandBiophysicsDirector,DivisionofCardiovascularMedicine

Co-Director,HeartInstituteStonyBrookUniversity,NewYork

KDIGO

PersistentCongestionandOutcomesinAcuteHeartFailure

•  Persistentclinicalandsub-clinicalcongestionatdischargeafteranAHFhospitalizationisassociatedwithworseoutcomes.

LucasC,etal.AmHeartJ.2000;140:840-847.

FonarowGC,etal.Circulation.1994;90(pt.2):1-488.

LogeartD,etal.JAmCollCardiol.2004;43:635-641

SignsandsymptomsPulmonaryCapillaryWedgePressure NatriureticPeptideLevels

KDIGO

•  6797HFsubjects(NYHAIII-IV)fromSOLVDTrials• MultivariateanalysisofsurvivalinsubjectswithbaselineserumCr<1.5vs.Cr1.5-2.0(Cr>2.0excluded)

•  Outcome RR 95%CIp-value

•  AllCauseMortality 1.41 1.25-1.59p<0.001PumpFailureDeath 1.5 1.25-1.8p<0.001SuddenDeath 1.28 0.99-1.63p=0.051

Driesetal.,1998

PredictiveValueOfRenalDysfunctionInHeartFailure

KDIGO

EffectofWorseningRenalFunctioninHospitalizedHeartFailurePatients

•  Averagelengthofstaywas7±4daysforcasesand5±3daysforcontrols(p=0.001)

•  Proportionofpatientswhostayedinthehospitalfor>10dayswas14%forcasesand3%forcontrols(p<0.05)

•  Hospitalmortalityratewas5.2%forcasesand1.6%forcontrols(p<0.05)

•  ButlerJetalAmHeartJ2004;147:331-338

KDIGO

Question• 68yearoldpatient

•  HTN,DM,CKD,andHF•  BaselineEF20%-comesinwithAHF•  BP110/70,HR82,Cr2.0•  OnLisinopril20qd,spironolactone25qd,carvedilol12.5bid,furosemide40bid,ASA

• Day1–startedonlasix80IVbid• MRA• ACEI•  LowerACEidose• Day2–BP106/72,Cr2.4,UOnetnegative800cc

KDIGO

Verycomplextopic

• Willnotdiscussepidemiology,outcomes,or(speculated)pathophysiologyofbothdiseasesco-existing

• Renalfunctionastargetoftherapy• RenalfunctionchangesinheartfailuretrialsKDIGO

Thestoryofworseningrenalfunction(i.e.changeinserumcreatinine>0.3mg/dl)

KDIGO

Buttheques3onis–whodecidedthatachangeinserumcrea3nine>0.3mg/dl–akaWRFisaproblemandatargetoftherapy?

KDIGO

Over700paperspublishedrelated

toWRF

KDIGO

Lesson

• Observationalstudies•  Greatforhypothesisgeneration•  Greatforsafetyassessment•  Notgreatforcausalityascertainment

• Understandpathophysiology•  Targetoftherapyshouldactuallybepresent,or• Atriskpopulation

• WRFWHF

KDIGO

Ifyouhavetimeonlytoread2pages!

KDIGO

Advantages

•  Morerapidremovaloffluidexcessandimprovementinsymptoms

•  Higherclearanceofsodiumload•  Isotonicfluidremoval•  Decreasedriskofelectrolyteabnormali3es(ie,hypokalemia)

•  Decreasedriskofworseningrenalfunc3on•  Lackofac3va3onoftheRASSandtheSNS•  Removalofproinflammatorycytokines•  ShortenedLOS•  Decreasedrateofreadmissionsforheartfailure

•  Significantcostperprocedure•  Nursingtrainingandstaffingrequired•  Excessivevolumeremovalresul3nginhypotension,WRF,andARF

•  Allergicreac3ontoextracorporealcircuit•  Catheter-relatedcomplica3ons(infec3onandthrombosis)

•  Hemorrhage-complica3ngsystemican3coagula3on

•  Hemorrhagefromvenousreturndisconnec3on

•  Airembolism•  Hemolysisandhyperkalemia

KDIGO

FreedomFromReadmissionforHF

100-

80-

60-

40-

20-

-102030405060708090

Days

Percen

tageofP

a3en

ts

FreeFromReh

ospitaliza3

on

No.Pa3entsatRiskUltrafiltra3onArm88858077757270666445StandardCareArm86837774666359585241

P=.037

Ultrafiltra3onArm(16Events)

StandardCareArm(28Events)

0

CostanzoMRetal.JAmCollCardiol.2007;49:675-683.

Ultrafiltra3onversusIVDiure3csforPa3entsHospitalizedforADHF:UNLOADTrial

KDIGO

ResourcesU3liza3onforHFin90Days

Resource UF SC PValue

Rehospitaliza3ons/Pa3ent 0.22 0.46 .037

Numberofrehospitaliza3ondaysperpa3ent 1.4 3.8 .022

Daysrehospitalized 123 330 .022

Unscheduledoffice+EDvisits(%) 21 44 .009

CostanzoMRetal.JAmCollCardiol.2007;49:675-683.

Ultrafiltra3onversusIVDiure3csforPa3entsHospitalizedforADHF:UNLOADTrial

Heartfailurefocusedoutcomes–needallcauserelatedhospitaliza3ons

KDIGO

EligibilityCriteria

KDIGO

Limitations

• PatientPopulation• CRSvs.diureticresistant• Robustdiuresis–notinCRS?

• SmallN• Treatmentdifferences

• 92(56-138)hr.forsteppedcare• 40(28-67)hr.forUF• UF–9%crossoverand30%IVdiuretics

KDIGO

Lessons

• Whilewearetryingtounderstandscienceandpathophysiology–needtogivealotofattentiontohowwillweanswerallthequestionswhen

•  A.Interestinphysiologyisdown•  B.Conductofclinicaltrialsisveryexpensive•  C.Regulatoryrequirementsandacademicsupport(includingnon-monetory)makesitevenmoredifficult

KDIGO

Lessons•  “Overt”diuresis

•  Metneed•  Currentdiureticsworks•  Aggressivesteppedcareapproachesneedtobeimplemented

• Curbtheenthusiasmforpragmatictrialstoappropriatecircumstances

• Understand •  Sub-clinicalcongestion•  Redistribution

KDIGO

•  12/2014to4/2016•  360patientsenrolledfrom22sites.

•  182patientsrandomizedtohigh-dosespironolactone

•  178tousualcare•  132placebo•  46continuedlowdose

spironolactone

StudyFlowandEnrollment–ATHENAHF

KDIGO

Results-PrimaryEndpointUsualCare Spironolactone P

LogNTproBNP

Baseline 8.23(7.58,8.94) 8.43(7.90,9.17)

96h(ordischarge) 7.64(6.93,8.45) 7.89(7.19,8.68)

Change -0.49(-0.98,-0.14) -0.55(-0.92,-0.18) 0.57

DyspneascaleCongestionscoreUrineoutputWeightLoopdiureticuseIn-hospitalWHF

KDIGO

HighDoseSpironolactoneinAcuteHeartFailureATHENA-HF

KDIGO

Lesson

• Whilewedon’tknowhowbesttosub-segmentpatients(clinical,imaging,biomarker,others)–progresswillrequireunderstandingpathophysiologicsubgroups.KDIGO

However

• DatalimitedtoGFR>30• HyperkalemiaandCKDintersection

• AwholeworldofheartfailurepatientswithGFR<30mlandthosewithhyperkalemianeedstobeexplored

KDIGO

Anotherissue

• Renalfunctionisimportanttounderstanddiseaseandtreatment• Becarefulinmakingrenalfunctionasendpoint

KDIGO

Sotoendonaverydepressingnote

• Didknowwhatcardio-renalsyndromeis?• HFrEF

• AlmostnodatainthosewithGFR<30• Hyperkalemia

• HFpEFandAHF• Nopositivetrialsofar-solimitedrenallessonsfromHFclinicaltrials

• Renalfunctionmaybeaprimarylearning,notnecessarilysecondary!

KDIGO

Onthebrightside

• KDIGOwillcontinuetohaveopportunitiestoinvitemetocoolplacestotalkaboutthisissuesfortheforeseeablefuture•  THANKYOU KDIGO

lessons learned from heart failure trials with respect to renal …€¦ · 04-02-2017 · lessons...

Documents